Project Summary The pathogenesis of chronic inflammatory bowel disease (IBD) is driven by dysregulation of both intestinal epithelial and immune cell functions. Chronic IBD places patients at increased risk for developing colitis- associated cancer (CAC), which has a poor prognosis. Limiting the severity and duration of inflammation and promoting its successful resolution is key to controlling colitis and preventing progression to cancer. Consumption of the ?-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), often in the form of fish oil, is encouraged to help control IBD and prevent development of colorectal cancer (CRC). Some clinical and pre-clinical studies have demonstrated benefit, but others have not, perhaps related to differential effects of specific components of fish oil. Specialized pro-resolving lipid mediators (SPMs) are biosynthesized from polyunsaturated fatty acids including EPA and DHA. 5-, 12-, and 15-lipoxygenases (LOX) are key enzymes in the formation of SPMs. SPMs limit pro-inflammatory signaling, and actively promote resolution in acute inflammation, including models of acute colitis. Much less is known about their actions in chronic inflammation and cancer. It has been clearly shown that loss of 15-LOX-1 occurs frequently in the development of colon cancer. Exactly how the resulting deficits in SPMs may be involved in the onset or maintenance of chronic inflammation and loss of normal intestinal epithelial functions is not completely understood. To better understand the role of SPMs in IBD/CAC, we are proposing in vivo studies in mouse models. Using two mouse models, we will take a comprehensive look at lipid mediators (LM) generated at different stages of colitis, dysplasia, and CAC, and the expression of biosynthetic enzymes and receptors, to identify patterns of where and when specific mediators are being generated, as well as how signaling is taking place between cells in the microenvironment. We will also manipulate the expression of 15-LOX-1 in colon epithelial cells in mouse models of IBD/CAC in order to determine how this impacts interactions between the epithelial and immune cells.